Radioactive medical devices

ABSTRACT

An implantable medical device according to the present invention comprises a body, such as a stent or a wire, having a radioisotope or non-radioactive precursor isotope associated with the body. The isotope preferably is disposed on the body using an efficient deposition method, such as an effusion cell. The method reduces the waste of costly isotopes and reduces the buildup of hazardous material in the apparatus. A metal layer may be deposited simultaneously with or subsequent to deposition of the isotope to encapsulate the radioactive isotope.

TECHNICAL FIELD

This invention relates to the field of radioactive medical devices, inparticular, to radioactive medical devices used to restore patency tocoronary arteries.

BACKGROUND OF THE INVENTION

Radioactive devices have found a host of uses in modern medicine,especially for treating cancerous growths and restenosis. Certainnon-malignant growths have been shown to be responsive to radiationtreatment, and may be amenable to treatment with an implantableradioactive medical device.

After balloon angioplasty, a metal tubular scaffold structure called astent may be permanently implanted to physically hold open the repairedcoronary artery. Unfortunately, up to 30% of such procedures result innarrowing or reclosure (restenosis) of the artery within six months toone year. One solution to the problem is to provide acute local,postoperative radiation treatment of the site using a catheter tippedwith iridium-192 radioisotope. In this method the iridium-192-tippedcatheter is placed at the arterial site for thirty to forty minutesafter stent deployment and then retracted. This type of acute high dosetreatment using gamma radiation has been found to substantially reducethe rate of subsequent restenosis, as noted in Wiedermann, J. G. et al.,"Intracoronary Irradiation Markedly Reduces Restenosis After BalloonAngioplasty in a Porcine Model", 23 J. Am. Coll. Cardiol., 1491-1498(May 1994) and Teirstein, P. S. et al., "Catheter-Based Radiotherapy toInhibit Restenosis After Coronary Stenting", 336 New England Journal ofMedicine, 1697-1703 (Jun. 12, 1997).

This method of irradiating the patient suffers from the hazardsassociated with the required high radiation intensity. In addition tothe surgeon, an oncologist and a radiation physicist are typicallyrequired for the procedure. A heavily shielded lead vault is needed toseparate the patient from the operating room personnel, and the task ofsafely inserting the catheter containing the intense source, which is onthe order of about 0.75 Curies, is particularly difficult. Ifirregularities occur in the procedure, the surgeon has relatively littletime to respond, and therefore emergency procedures must bewell-rehearsed. This method, while possible in a research environment,may not be practical for many clinics and community-based hospitals.

An alternate method of addressing the restenosis problem is to embedwithin the structural material of the stent itself a radioactivematerial, such as described by Fischell et al. in U.S. Pat. No.5,059,166 (the '166 patent) and in U.S. Pat. No. 5,176,617 (the '617patent). The '166 and '617 patents also describe methods ofelectroplating a radioactive material on the structural material of thestent. These methods have certain drawbacks. Placement of radioactivematerial within the structural material of the stent can presentfabrication difficulties with respect to radiation exposure of workersduring the manufacturing process. The electroplating process may resultin poor adhesion of the radioactive material, which could delaminateduring insertion or stent expansion. Although electroplating is aninexpensive technique, electroplating does not work well on devices madeof stainless steel or nitinol, and there are many desirable radioactiveelements that cannot readily be electroplated. Also, electroplating andmany other types of coating technologies, for example sputtering,cathodic arc, or magnetron sources as taught by Good, et al. in U.S.Pat. No. 5,342,283, generally require a relatively large quantity ofspecially fabricated and prepared feedstock material to be successfullyemployed. These technologies are ineffective when only a few milligramsof feedstock are available.

Another method mentioned by Fischell and investigated by Laird, J. R. etal., in "Inhibition of Neointimal Proliferation with a Beta ParticleEmitting Stent", Circulation 1996; 93:529-536 (the `Laird article`), isto impregnate titanium stents with up to thirty atom percent of stablephosphorous and subsequently activate the entire stent in a nuclearreactor to form the radioisotope ³¹ P within the titanium structuralmaterial. One of the disadvantages of the Laird method is that themassive quantity (30 atom %) of phosphorous required to achieve even0.15 microcuries from ³¹ P may severely alter the structural strength ofthe stent itself.

In the preferred embodiment of the '166 and '617 patents, the structuralmaterial in the body of the stent is alloyed with a non-radioactiveprecursor element and then subsequently activated in a nuclear reactorto generate the radioactive isotope. However, if the body of the stentor any similar implantable medical device (including, for example,cancer irradiation needles, shunts, vascular grafts, bone screws, andfemoral stem implants) contains significant quantities of iron and/orchromium, as is true of stainless steel, for example, then neutronactivation produces long-lived radioisotopes which emit a substantialquantity of gamma rays. The emission of these gamma rays is notdesirable in a permanent implant because of the resulting high totalbody dose of radiation.

Another method for embedding the desired radioisotopes in the body ofthe stent is known as ion implantation. This has been described byJanicki et al. ("Production and Quality Assessment of Beta Emitting ³² PStents for Applications in Coronary Angioplasty", 42nd Annual Meeting ofthe Canadian College of Physicist in Medicine, Jun. 20-22, 1996,University of British Columbia, Vancouver, Canada.) and by Fischell etal. (Low-Dose, β-Particle Emission From `Stent` Wire Results inComplete, Localized Inhibition of Smooth Muscle Cell Proliferation"Circulation 90 :1994) specifically for ³² P-containing stents. Aradioactive ion source for ³² P is described in co-pending applicationU.S. Ser. No. 08/887,504, which is hereby incorporated by reference.

Ion implantation consists of ionizing individual atoms of theradioactive species, accelerating the charged atoms through a highvoltage, and directing the resultant beam onto the surface of a device.The high velocity of the accelerated atoms causes the impinging atoms tobe embedded below the surface of the device and thus to becomeincorporated within the body of the device. The ion implantation processmay utilize a magnetic mass filter device which separates the atoms ofthe desired radioisotope from the large family of isotopes that may beproduced when the atoms are first ionized. Since only a relatively smallquantity of radioactive atoms are required to produce the desiredintensity of radioactivity, it is possible to avoid the problemencountered in the Laird method, wherein a high concentration ofalloying material may modify the structural strength of the devicematerial.

While ion implantation has been successfully demonstrated to embedradioactive ³² P within a stent, ion implantation of other radioactiveisotope species is more difficult. For example, the radioactive isotope¹⁰³ Pd requires as much as 30 times the activity level of ³² P for asimilar therapeutic effect, thus making the task of ion-implanting ¹⁰³Pd much more difficult. In particular, the radioactive isotope feedstockmust be utilized much more efficiently than usual (typically between 0.1and 0.5%) in order to avoid accumulating large quantities of radioactivepalladium waste throughout the ion implanter. Radioactive isotopes areexpensive, and the waste of most of the radioactive material is bothcostly and hazardous because of the accumulated radioactivecontamination which escapes being ion implanted into the medical device.In addition, there is also an increased risk of radiation dose topersonnel who would have to periodically maintain the inefficient,radioactive evaporation apparatus.

Although numerous techniques have been devised to coat or implantradioactive material onto medical devices, none of these techniquestransfer the radioactive material with a high efficiency. As a result,these techniques are inadequate, particularly when only a few milligramsof source material are available.

SUMMARY OF THE INVENTION

The invention comprises methods for manufacturing radioactive medicaldevices which comprise a body having disposed thereon a coating of oneor more radioactive isotopes or non-radioactive precursor isotopes, andapparatus for carrying out the methods. This invention further comprisesimplantable medical devices manufactured by these methods. The methodsand apparatus allow radioactive material or non-radioactive precursormaterial to be deposited on the body of a medical device with highefficiency, and further confer the ability to recycle the radioactive orprecursor material that is not constructively deposited during theprocess.

In one embodiment, the method comprises disposing a radioisotope ornon-radioactive precursor isotope on a body under conditions sufficientfor the isotope to become associated with the body, e.g., by vapordeposition. The radioisotope or non-radioactive precursor isotope maythen be encapsulated by a metal coating either simultaneous with orsubsequent to disposing the radioisotope or non-radioactive precursorisotope on the body. Optionally, the metal coating may comprise abiocompatible material, or a biocompatible material may be disposed ontothe device following encapsulation by the metal coating. In certainembodiments, an adhesion layer may be deposited between the isotope andthe body.

A body useful in the medical device of the present invention comprisesany structure, device, or article having characteristics such asstability, resiliency, structure, and shape suitable for use as animplantable radioactive medical device. The body may comprise, forexample, a stent, seeds, wire, or other articles suitable forimplantation in a patient to deliver a localized dose of radiation. Thebody may comprise a metal, metal alloy, or ceramic. For example, atitanium alloy, titanium-vanadium-aluminum alloy, rhodium, vanadium,palladium, rhenium, aluminum, nickel, nitinol (NiTi), stainless steel,and alloys of stainless steel such as type 404 steel may be used.Preferred metals and metal alloys comprise stainless steel, rhodium,palladium, titanium, Ti-6-4 (90% titanium, 6% vanadium, and 4%aluminum), and nitinol (50% nickel and 50% titanium). Ceramics useful inthe present invention may comprise, for example, quartz (silicondioxide), alumina (aluminum oxide), titania (titanium dioxide), andzirconia (zirconium oxide).

In a currently preferred embodiment, the body comprises a stent, saidstent being a medical device that can be placed within the lumen of atubular structure to provide support during or after anastomosis orcatheterization, or to assure patency of an intact but contracted lumen.FIG. 1 shows an example of a stent which can be used in coronaryarteries. In this embodiment, the shape of the body may be a tubularmesh shape, a helical coil shape, or any of a variety of other shapessuitable for a stent.

In a preferred embodiment, the present method comprises depositing aradioactive, costly, or otherwise precious or hazardous material in anefficient manner by the judicious selection of the isotope source. Theisotope source preferably provides the radioisotope or non-radioactiveprecursor isotope as a focused stream of vapor. This may beaccomplished, for example, by heating the isotope using a device calledan effusion cell to vaporize the isotope. An effusion cell comprises athermally heatable enclosed volume, within which the radioactive isotopeor non-radioactive precursor isotope is placed, together with a smalldiameter aperture through which the resulting vapor is expelled. Aneffusion cell differs from an ordinary evaporator in that most or,preferably, all surfaces within the enclosed volume are heated to atemperature sufficient to sublimate the evaporant. The vapor is expelledinto a vacuum chamber, and thus the interior of the effusion cell isalso at vacuum pressure. The effusion cell provides a flow of vapor inthe form of condensable gas which may be utilized to coat a surface. Inpreferred embodiments, the layer of radioisotope or non-radioactiveprecursor isotope is less than about 250 Å thick, even more preferablybetween about 50 Å and about 100 Å.

Stable, non-radioactive precursor isotopes useful in the invention maybe any isotope which, upon thermal neutron activation, generates aradioactive isotope having the desired emission profile. Exemplaryprecursor isotopes having this property include, for example,ytterbium-168, barium-130, phosphorus-31, palladium-102, yttrium-89,rhenium-185, and rhenium-187. Mixtures or combinations of more than oneprecursor isotope may be used.

Radioisotopes useful in the present invention may be any therapeuticallyor prophylactically effective radioactive material. Preferredradioisotopes comprise, for example, phosphorus-32, iodine-125,palladium-103, yttrium-90, cesium-131, and ytterbium-169. Mixtures orcombinations of more than one type of radioactive isotope may be used inthe device.

When more than one type of radioactive isotope or non-radioactiveprecursor isotope is deposited on the medical device, separate effusioncells whose temperatures, and thus evaporation rates, are individuallycontrolled, may be employed for each isotope.

The amount of radioisotope deposited on the body may be monitored bysubstantially simultaneously detecting the amount of radioactivityemitted by the body during deposition of the radioisotope.

In embodiments wherein a non-radioactive precursor isotope is deposited,the isotope is activated by exposing the device to a source of thermalneutrons to generate a radioactive isotope having the desired emissionprofile. The body and any coatings disposed thereon preferably will notinclude materials, such as stainless steel, chromium, or nickel, whichmay generate undesirable radioisotopes when exposed to a source ofthermal neutrons, unless the duration of the exposure is limited.

An additional metal layer also may be deposited onto the body toencapsulate the radioactive material. Examples of such metals comprise,but are not limited to, titanium, gold, tantalum, carbon,titanium-aluminum-vanadium alloy, stainless steel, cobalt-chrome alloy,cobalt-chrome-molybdenum alloy, rhodium, lead, silicon, copper,platinum, and palladium. Preferred materials comprise titanium, titaniumalloy, gold, copper, tantalum, stainless steel, cobalt-chrome alloy,platinum, and palladium. The metal layer may be deposited simultaneouslywith or subsequent to the deposition of the radioisotope ornon-radioactive precursor isotope. Alternately, the radioisotope ornon-radioactive precursor isotope may be ion-implanted into theencapsulated metal layer. The metal layer is produced from a sourceseparate from the isotope source. This separate source may employ any ofa variety of well known coating methods, such as thermal boatevaporation, electron beam evaporation, sputtering, or another effusioncell. When the metal layer is deposited after deposition of the isotope,the metal layer may be deposited in a separate step or in a separatedevice from the isotope layer.

The metal layer may be of any thickness that provides the desiredencapsulation. The coating thickness is preferably as thin as possible,because implantable medical devices, such as stents, may be flexedsignificantly during deployment, and a very thin coating is less likelyto affect the mechanical properties of the device or to be affected bythe flexing. For example, the metal layer preferably is less than about50,000 Å thick, more preferably less than about 10,000 Å thick.

An adhesion layer may be deposited onto the body before deposition ofthe istope. The adhesion layer comprises a material, preferably a metal,which improves adhesion of the isotope to the body. The adhesion layerpreferably comprises at least one material selected from the groupconsisting of aluminum, silicon, titanium, vanadium, palladium,manganese, copper, nickel, gold, and rhodium. Preferred materialsinclude titanium and gold. The adhesion layer may be deposited by any ofa variety of well known coating methods, such as thermal boatevaporation, electron beam evaporation, sputtering, or another effusioncell. The adhesion layer may be deposited in a separate device from theisotope layer or the metal layer. The adhesion layer may be of anythickness that improves the adhesion of the isotope to the body,preferably as thin as possible to avoid altering the physical propertiesof the device. For example, the adhesion layer preferably is less thanabout 2000 Å thick, more preferably less than about 500 Å thick.

Another aspect of the present invention relates to apparatus formanufacturing medical devices such as described above. Such an apparatuscomprises a source of a radioisotope or non-radioactive precursorisotope which provides a focused source of the isotope, such as aneffusion cell, and a support for holding a medical device to be coated.Preferably, the support is movable to present different portions of thedevice to the isotope source. The device may further comprise a sourcefor a metal coating. This source may be capable of depositing a coatingof metal onto the device either during or after deposition of theisotope.

In the apparatus, the implantable medical device preferably is movablerelative to the narrow stream of coating material in order to uniformlycoat the desired surface area of the device. Exemplary motions mayinclude either or both rotation and linear translation, depending on theshape of the implantable medical device. The flux of the radioactiveisotope or non-radioactive isotope may not necessarily impinge on themedical device body at precisely the same time or location as the metalcoating, but it is desired that a selected ratio between the depositionrate of each type of flux should be maintained to effect encapsulation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a side-view and a cross-section of a single wire of atubular mesh stent according to the present invention.

FIG. 2 illustrates an effusion cell for a radioactive isotope.

FIG. 3 illustrates coating a stent using an effusion cell together witha metal sputtering gun.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Many medical devices are made from metals such as titanium alloy,nitinol (NiTi), or stainless steel. FIG. 1 shows an example of such adevice, called a stent, which is used for maintaining the patency ofcoronary arteries. The stent is an example of an implantable medicaldevice whose efficacy can be usefully improved by the addition of aradioactive isotope.

Radioactive isotopes are inherently hazardous and costly. Therefore, itis important to utilize radioactive isotopes as efficiently as possiblein order to minimize resultant radioactive waste, the cost of materials,and the hazards associated with handling them. It is preferred thatprocesses that add radioactive isotopes to implantable medical devicesutilize and transfer the radioactive isotopes to the implantable medicaldevices as efficiently as possible. While many such processes are knownto exist, each tends to be specialized for working with only one or alimited range of elements. A useful, somewhat more general method is touse vapor deposition to deposit a coating.

The present method comprises a high-efficiency vapor desposition methodutilizing an effusion cell to apply the precursor isotope orradioisotope. The term `efflusion cell` refers to a cell or furnace forcreating a vapor from a source which can then be deposited on asubstrate. The method comprises heating a radioactive isotope in aneffusion cell under conditions sufficient to vaporize atoms of theisotope, and disposing a layer of the atoms of the isotope on a body.The method may further comprise disposing a layer of metal onto thebody. The metal coating may be deposited subsequent to or substantiallysimultaneously with disposing a layer of the isotope on the body. Themethod may further comprise disposing an adhesion layer onto the bodyprior to disposing the later of the isotope on the body.

The effusion cell was originally devised by Knudsen as a research toolfor the precision measurement of vapor pressure. See for example"Handbook of Thin Film Technology", Leon I Maissel and Reinhard Glang,McGraw-Hill Book Company, New York, 1970, pp. 1-26 to 1-28. The effusioncell is usually characterized by a low evaporant flux output spread overa relatively small area. Most high-throughput industrial coatingprocesses require a much greater evaporant flux for cost efficiency, andthus the effusion cell is normally employed solely for high precision,non-radioactive coating applications, as are common in semiconductorresearch using molecular beam epitaxy equipment.

The effusion cell comprises an enclosed, thermnally heated volume whichpossesses a small diameter orifice for vapors to be emitted. The orificeis preferably less than about 3 mm in diameter and preferably about1-1.5 mm in diameter. A narrow, conically expanding jet of vaporemanates from the orifice. FIG. 2 shows a diagram of a typical effusioncell 1. The cell has an electrical resistance heating element 2, thermalinsulation 3, and orifice 4. The enclosed heated volume is used to holdthe radioactive isotope 5 to be evaporated.

In the method of the invention, the temperature of the effusion cell maybe controlled to modify or maintain the production rate of radioactivevapor. Additionally, other factors, such as the size of the remainingvapor-emitting particles of radioactive isotope material, may alsoaffect the production rate of radioactive vapor. For this reason, isimportant to independently measure the accumulated intensity ofradioactive nuclear radiation coming from the medical device while it isbeing coated in order to establish when the coating has becomesufficiently thick and the nuclear radiation has become sufficientlyintense.

The present method comprises the use of an effusion cell specificallyfor the application of a radioactive or precursor isotope to a medicaldevice resulting in a high utilization efficiency of the evaporant overa small coating area. Conventional evaporation devices, such as electronbeam evaporators or thermal boat evaporators, evaporate atoms intoapproximately a 2π solid angle (a hemisphere). Most of the radioactivematerial thus would be wastefully lost on walls of the vacuum chamber oron shields, since the devices to be coated may occupy only a smallportion of this hemispherical zone. The effusion cell can emit coatingmaterial into approximately a 0.02π solid angle and thus is far moreefficient for coating small devices, aiming as much as about 10-50% ofthe evaporated radioactive material directly onto the small implantablemedical device, rather than wastefully onto shields or walls.

This efficiency is critical because the cost of radioactive isotopes isvery high. Additionally, some radioactive isotopes of importance, suchas ¹⁰³ Pd, are most easily fabricated from an isotopically enrichednon-radioactive precursor, such as ¹⁰² Pd, and this costly precursorfeedstock is only available in milligram quantities. Coating manydevices with a small quantity of radioactive material can beaccomplished using a process having very high feedstock utilizationefficiency.

An additional advantage of the present process utilizing an effusioncell is that the waste-coated radioactive material can be easilycollected because the surface area of the shields used for collectioncan be kept very small. The waste radioactive material and the shield onwhich it has been deposited can be placed within the effusion furnaceand re-evaporated multiple times, effectively recycling the wastematerial, thus further increasing utilization efficiency to near 100%. Ashield may be fabricated from any convenient refractory material. In apreferred embodiment, the shield is made from thin, e.g., about 0.001inch thick, tantalum, which has a very low vapor pressure at theevaporation temperatures of interest for medically useful radioactiveisotopes, and thus does not substantially contribute to the evaporatedcoating from the effusion furnace.

For small implantable medical devices, such as stents, it is preferableto position the device as close to the orifice of the effusion cell aspossible for minimum dispersion of the jet. This distance is preferablybetween about 1-2 cm for a stent. It is also preferable to provide agroup of shields that can serve to collect and accumulate anyradioactive isotope coating that may miss being deposited onto thesurface of the implantable medical device. The shields are preferablyfabricated from a thin foil made from a refractory material. Abiocompatible material, such as tantalum or titanium, is preferred. Thefoil thickness is preferably as thin as possible, typically about 0.001inches in thickness, so that the foil is easily flexible and bendable.The area of the foil shields is preferably as small as possible in orderto facilitate bending the foil, together with any accumulated coating ofradioactive isotopes, and placing the foil within the heated volume ofthe effusion furnace. The refractory material of the heated foilpreferably should have a vapor pressure at least about 2 orders ofmagnitude less than that of the radioactive isotope at the sametemperature so that the radioactive isotope can be substantially theonly species being emitted by the effusion furnace.

FIG. 3 illustrates a vacuum chamber 10 containing an effusion cell 1 fordepositing the radioactive isotope coating, refractory material shields11, a stent 12 to be coated with either or both a radioactive isotopematerial and a metal, and a sputtering gun 13 for depositing a metalcoating. The sputtering gun 13 may be operated either simultaneouslywith the effusion cell 1 or sequentially with the sputtering gunproviding an overcoat after the radioactive isotope coating has beendeposited. In some embodiments, it may be desirable to coat onlyspecific surfaces of the stent 12 or other implantable medical device.Therefore, it is preferred that a system for manipulating theorientation of the stent 12 be supplied in order to present all of thedesired surfaces to the jet of radioactive vapor from the effusion cell1 and the sputtering gun 13.

The sputtering gun 13 is one method for applying an encapsulating metalcoating. Other methods which may be employed include, for example,thermal boat evaporation, electron gun evaporation, or a separate,non-radioactive effusion furnace. The cost of the metal encapsulanttypically is not nearly as great as for the radioactive isotope, andthus less efficient coating methods may be usefully employed forconvenience. Furthermore, because the material is not radioactive,material lost on the walls of the apparatus does not present a hazard.It is preferred that a separate set of shields 14 be used to restrictthe path of the flux of vapor from the sputtering gun 13 in order tobetter control the metal coating deposition rate relative to that of theradioactive isotope coating from the effusion furnace 1. While theprecise relative coating rates depend on the specific materials beingemployed, it is preferred that the metal coating deposition rate bebetween about 1 and about 10 times that of the radioactive isotopecoating deposition rate.

The deposition rate of the effusion cell 1 is preferably controlled byvarying the temperature. The deposition rate of the sputtering gun 13 orits equivalent method is preferably controlled using means typical ofthe selected coating method. For example, the sputtering gun 13deposition rate is controlled by the applied power or by the distancebetween the sputtering gun and the stent 12. Additionally, finer controlmay be achieved preferably by means of a variable mechanical shutter.

It is preferred that the radioactive radiation being emitted by theaccumulated radioactive isotope coating be measured while theradioactive isotope coating is being deposited. FIG. 3 illustrates athin window 15 in the vacuum chamber 10 through which the nuclearradiation can substantially pass. While such a window can be fabricatedfrom a variety of materials and thicknesses depending on the type ofnuclear radiation being emitted by the radioactive isotope coating, auseful vacuum window for most cases could be fabricated of about 0.001inch thick mylar. A collimator 16 is used to permit the nuclearradiation detector 17 to view a limited region on the surface of thestent 12. The collimator 16 is preferred in order to minimize theviewing of radioactive isotope coating that may be located on a shield11, rather than a stent 12. The measurement of the nuclear radiationusing detector 17 may preferably be used to determine when the desiredthickness of radioactive isotope coating has been accomplished.

A radioactive medical device manufactured by the process described abovecomprises a body having a layer of a radioisotope or non-radioactiveprecursor isotope disposed thereon. Exemplary precursor isotopes whichcan be activated by exposure to a source of thermal neutrons include,for example, ytterbium-168, barium-130, phosphorus-31, palladium-102,yttrium-89, rhenium-185, and rhenium-187. Preferred radioisotopescomprise, for example, phosphorus-32, iodine-125, palladium-103,yttrium-90, cesium-131, and ytterbium-169. Mixtures or combinations ofmore than one precursor or radioactive isotope may be used. In preferredembodiments, the layer of radioisotope or non-radioactive precursorisotope is less than about 250 Å thick, even more preferably betweenabout 50 Å and about 100 Å.

A radioactive medical device may further comprise an adhesion layer. Theadhesion layer comprises a material which improves adhesion of theisotope to the body. The adhesion layer preferably comprises at leastone material selected from the group consisting of aluminum, silicon,titanium, vanadium, palladium, manganese, copper, nickel, gold, andrhodium. Preferred materials include titanium and gold. The adhesionlayer may be of any thickness that improves the adhesion of the isotopeto the body, preferably as thin as possible to avoid altering thephysical properties of the device. For example, the adhesion layerpreferably is less than about 2000 Å thick, more preferably less thanabout 500 Å thick.

The device may further comprise a layer of metal to encapsulate theradioactive isotope. Examples of suitable metals comprise, but are notlimited to, titanium, gold, tantalum, carbon, titanium-aluminum-vanadiumalloy, stainless steel, cobalt-chrome alloy, cobalt-chrome-molybdenumalloy, rhodium, lead, copper, platinum, and palladium. Preferredmaterials comprise titanium, gold, tantalum, titanium alloy, stainlesssteel, cobalt-chrome alloy, platinum, and palladium. The metal layerpreferably is less than about 50,000 Å thick, more preferably less thanabout 10,000 Å thick.

In a preferred embodiment for manufacturing a radioactive medicaldevice, an adhesion layer is first disposed on a body. The adhesioncoating may be of any material set forth above, preferably titanium orgold, and is preferably less than about 500 Å thick. The adhesioncoating may be disposed on the body by any means set forth above, eitherin an apparatus having an effusion cell or in any other apparatus.

The radioactive or non-radioactive isotope then is deposited on theadhesion layer, preferably using an effusion cell. The isotope may beany of the radioactive or non-radioactive isotopes set forth above,preferably phosphorus-32, palladium-103, yttrium-90, cesium-131, orytterbium-169. In preferred embodiments, an even coating of the isotopemay be achieved by moving the body with respect to the effusion cell topresent all surfaces of the body to the flux of atoms of the isotope. Ina preferred embodiment, an encapsulating metal layer is depositedsubstantially simultaneously with the isotope to maximize the retentionof atoms of the isotope. The metal layer may be deposited by anytechnique set forth above, preferably by sputtering. The metal layer maycomprise any metal described above, preferably titanium, gold, or atitanium alloy. When the isotope is a radioisotope, the amount of theisotope deposited may preferably be controlled by monitoring theradioactivity of the device during deposition of the radioactiveisotope. If the isotope is deposited prior to deposition of the metallayer, the layer of the isotope is preferably less than about 250 Å. Themetal layer is preferably less than about 50,000 Å thick.

If a non-radioactive isotope is used in the above procedure, the bodycomprising the non-radioactive isotope is preferably exposed to a sourceof thermal neutrons under conditions sufficient to generate aradioisotope. If the isotope is deposited separately from the metallayer, the non-radioactive isotope may be activated before or after themetal layer is disposed on the body.

The following examples further illustrate the invention, and are notintended to be limiting in any way.

EXAMPLE 1

This example illustrates the procedure used to coat a stainless steelcoronary stent of approximately 18 mm in length and 2 mm in diameter.The stent first was coated with an adhesion coating comprising 2000 Å ofpure titanium using magnetron sputtering in a non-radioactive apparatusseparate from the apparatus containing a radioactive effusion cell. Thestent coated with the adhesion coating then was transferred to a vacuumsystem containing an effusion cell.

The effusion cell was loaded with about 0.003 grams of radioactivepalladium metal powder. A sputter gun with a pure titanium cathode wasused for depositing the metal coating. The vacuum chamber was evacuatedto a pressure less than about 1×10⁻⁵ Torr. The effusion cell was heatedto 1250° C. The 18 mm long stent was both rotated and linearlytranslated while being coated for approximately 2 hours. The sputter gunwas simultaneously operated at 4 millitorr and 150 Watts. A NaI(T1)nuclear radiation detector was used to determine the end of theradioactive isotope coating period, when the count rate for palladiumx-rays around 20 keV reached 150 counts per second. The effusion cellwas turned off, and the sputter gun continued to operate for another 15minutes to ensure that the radioactive isotopes were fully embedded intitanium.

EXAMPLE 2

The following procedure describes a process for making a high activityradioactive wire used for temporary intravascular brachytherapy byion-implanting a non-radioactive precursor.

A copper wire of 99.999% purity and 0.008" in diameter wassimultaneously ion-implanted with ¹⁶⁸ Yb using a mass-analyzed ionimplanter and simultaneously coated with copper evaporated from anelectron beam evaporator. This procedure effectively encapsulates the¹⁶⁸ Yb atoms within the copper coating and also compensates for thesputter loss from the wire by the high energy ion beam. This procedureis similar to that used to ion-implant a zirconia coating, as describedmore fully in U.S. Pat. No. 5,383,934 to A. J. Armini and S. N. Bunker,assigned to the common assignee.

The ¹⁶⁸ Yb ion beam had a current density of 0.3 μA/cm² at a kineticenergy of 60 keV. In 14.8 hours, 3×10¹⁵ atoms of ¹⁶⁸ Yb per centimeterof wire length were embedded in the wire. The copper evaporation ratewas 0.5 μÅ/s, depositing a coating approximately 2.6 microns thick.

The wire was then placed in the Oak Ridge high flux isotope reactor at athermal flux of 2×10¹⁵ neutrons/cm² s for two weeks. After a 10-daycooling period, the 12-hour half-life radioisotopes produced from thecopper were essentially gone and the wire emitted 126 mCi/cm length ofpure ¹⁶⁹ Yb radiation. Six or more wires of this strength are sufficientto perform intravascular brachytherapy after angioplasty.

Equivalents

While the invention has been disclosed in connection with the preferredembodiments shown and described in detail, various equivalents,modifications, and improvements will be apparent to one of ordinaryskill in the art from the above description. Such equivalents,modifications, and improvements are intended to be encompassed by thefollowing claims.

What is claimed is:
 1. A method for manufacturing a radioactive medicaldevice, comprisingheating a radioactive isotope in an effusion cellunder conditions sufficient to vaporize atoms of the isotope; anddisposing a layer of the atoms of the isotope on a body.
 2. The methodof claim 1, wherein the layer of atoms disposed on the body is less thanabout 250 Å thick.
 3. The method of claim 1, wherein the radioactiveisotope is selected from the group consisting of ³² P, ⁹⁰ Y, ¹⁰³ Pd, ¹²⁵I, ¹³¹ Cs, and ¹⁶⁹ Yb.
 4. The method of claim 1, wherein the intensityof radioactivity of the atoms disposed on the body is measured using anuclear radiation detector substantially simultaneously to disposing thelayer of the atoms on the body.
 5. The method of claim 1, furthercomprising disposing an adhesion layer onto the body prior to disposingthe layer of the atoms of the isotope on the body.
 6. The method ofclaim 1, further comprising disposing a metal layer onto the body. 7.The method of claim 6, wherein disposing the metal layer occurssubstantially simultaneously with depositing the layer of the atoms ontothe body.
 8. The method of claim 6, wherein disposing the metal layer isperformed by a method selected from the group consisting of thermal boatevaporation, electron beam evaporation, sputtering, and a secondeffusion cell.
 9. The method of claim 6, wherein said metal layercomprises a biocompatible material including one or more materials fromthe group consisting of titanium, titanium alloy, gold, copper,tantalum, stainless steel, cobalt-chrome alloy, platinum, and palladium.10. The method of claim 6, further comprising disposing an adhesionlayer onto the body prior to disposing the layer of the atoms of theisotope on the body.
 11. The method of claim 6, wherein the metal layerencapsulates the radioactive isotope.
 12. A method for manufacturing amedical device, comprisingheating a non-radioactive precursor isotope inan effusion cell under conditions sufficient to vaporize atoms of theisotope; and disposing a layer of the atoms of the isotope on a body.13. The method of claim 12, wherein the layer of atoms disposed on thebody is less than about 250 Å thick.
 14. The method of claim 12, whereinthe non-radioactive precursor isotope is selected from the groupconsisting of ³¹ P, ⁸⁹ Y, ¹⁰² Pd, ¹⁸⁵ Re, ¹⁸⁷ Re, ¹³⁰ Ba, and ¹⁶⁸ Yb.15. The method of claim 12, further comprising exposing the body havingthe layer of atoms disposed thereon to a source of thermal neutronsunder conditions sufficient to activate the atoms of the isotope. 16.The method of claim 12, further comprising disposing an adhesion layeronto the body prior to disposing the layer of the atoms of the isotopeon the body.
 17. The method of claim 12, further comprising disposing ametal layer onto the body.
 18. The method of claim 17, wherein disposinga metal layer occurs substantially simultaneously with disposing thelayer of the atoms onto the body.
 19. The method of claim 17, whereinsaid metal layer comprises one or more materials selected from the groupconsisting of titanium, titanium alloy, gold, copper, tantalum,stainless steel, cobalt-chrome alloy, platinum, and palladium.
 20. Themethod of claim 17, wherein disposing a metal layer is performed by amethod selected from the group consisting of thermal boat evaporation,electron beam evaporation, sputtering, and a second effusion cell. 21.The method of claim 17, wherein the metal layer does not comprise amaterial which neutron activates to long-lived radioisotopes.
 22. Themethod of claim 17, wherein the metal layer encapsulates thenon-radioactive precursor isotope.
 23. A medical device manufacturedbyheating a non-radioactive precursor isotope in an effusion cell underconditions sufficient to vaporize atoms of the isotope; and disposing alayer of the atoms of the isotope on a body.
 24. The medical device ofclaim 23, which is rendered radioactive by exposing the device to asource of thermal neutrons under conditions sufficient to activate theprecursor isotope.
 25. A radioactive medical device manufacturedbyheating a radioactive isotope in an effusion cell under conditionssufficient to vaporize atoms of the isotope; and disposing a layer ofthe atoms of the isotope on a body.